CN1686457A - Chinese medicina composition for treating algomenorrhea and its preparation method - Google Patents
Chinese medicina composition for treating algomenorrhea and its preparation method Download PDFInfo
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Abstract
A Chinese medicine for treating primary menalgia is prepared from 7 Chinese-medicinal materials including red sage root, white peony root, fennel, liquorice root, etc. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition for the treatment of dysmenorrhea and preparation method thereof, the especially application of this Chinese medicine composition in the medicine of the preparation treatment source property sent out dysmenorrhea.
Background technology
Dysmenorrhea also claims abdominal pain during menstruation,, frequently-occurring disease common for gynecological.Clinical symptoms is through row lower abdomen pain, follows menstrual cycle and shows effect.The patient generally shows as the few China of shallow complexion, and food is received not good enough, and lower abdomen is arrested tight, soreness of the waist and knees, and the emotion irritability, irritability, si dol urg also pale complexion, cold extremities, cold sweat can occur, even faints.Dysmenorrhea makes the women very painful, has a strong impact on their study, work and life.Dysmenorrhea can be divided into two kinds of constitutional and Secondary cases clinically.The stomachache, genitals does not have the significant organic pathological changes to the source property sent out dysmenorrhea, claims primary dysmenorrhea again before and after companion's menstruation.According to sampling survey in 1980, the dysmenorrhea sickness rate of China was 33.19%, and wherein the property sent out dysmenorrhea in source accounts for 36.06%, and have a strong impact on work, learner accounts for 13.59%.The successive dynasties traditional Chinese medical science was done many trial to this disease, and was not satisfactory but the doctor is imitated.In recent years,, control, control, Therapeutic Method such as the side of being fixed into, special side's proved recipe also occurred by the menstruation cycle theory except the differentiation of symptoms and signs for classification of syndrome opinion for TREATMENT OF DYSMENORRHOEA.Except adopting traditional decoction, also medicine is made oral liquid or medicated powder is incapsulated, or the water dosage form of taking after mixing it with water, patient is safe and effective to dysmenorrhea, embodied letter, just, the characteristics tested.In sum, present Chinese medicine dysmenorrhea aspect, determined curative effect is reliable.Dosage forms such as granule, oral liquid, powder, soaking agent, taking convenience has and uses prospect and exploitation to be worth preferably, is worth further research.
Summary of the invention
The object of the present invention is to provide a kind of Chinese medicine composition for the treatment of dysmenorrhea.
Another object of the present invention is to provide a kind of preparation method of this Chinese medicine composition.
A further object of the invention is to provide the application of this Chinese medicine preparation in the medicine of the preparation treatment source property sent out dysmenorrhea.
Chinese medicine composition provided by the invention is prepared from by the following weight proportion raw material:
Radix Salviae Miltiorrhizae 60-120 part Radix Paeoniae Alba 60-120 part Rhizoma Cyperi (processed with vinegar) 24-48 part Rhizoma Corydalis (processed with vinegar) 40-80 part
Fructus Toosendan (stir-fry) 20-40 part Fructus Foeniculi 10-20 part Radix Glycyrrhizae (processed with honey) 24-48 part
Chinese medicine composition of the present invention preferably is prepared from by the following weight proportion raw material:
Radix Salviae Miltiorrhizae 70-90 part Radix Paeoniae Alba 70-90 part Rhizoma Cyperi (processed with vinegar) 25-36 part Rhizoma Corydalis (processed with vinegar) 40-60 part
Fructus Toosendan (stir-fry) 20-30 part Fructus Foeniculi 10-15 part Radix Glycyrrhizae (processed with honey) 25-36 part
Chinese medicine composition of the present invention preferably is prepared from by the following weight proportion raw material:
50 parts of 30 parts of Rhizoma Corydalis of Radix Salviae Miltiorrhizae 75 portions of Rhizoma Cyperis of 75 portions of Radix Paeoniae Albas (processed with vinegar) (processed with vinegar)
30 parts in Fructus Toosendan (stir-fry) 12.5 portions of Radix Glycyrrhizaes of 25 parts of Fructus Foeniculi (processed with honey)
Chinese medicine composition of the present invention can be prepared into various preparations by the ordinary skill in the art.
The present invention also provides the preparation method of preferred this Chinese medicine composition, and this method comprises the steps:
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35-1.38 (60-65 ℃), drying under reduced pressure (0.08Mpa, 60-70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet, capsule etc. according to this area routine techniques.
The present invention is on the basis of research tradition Chinese herbal medicine, through test for many years, integrates theory with practice, and the advanced study and training summary draws with great concentration.Medicine of the present invention coaches with theory of Chinese medical science, has the effect of blood circulation promoting and blood stasis dispelling, promoting the circulation of QI to relieve pain, and for the treatment dysmenorrhea, especially the property sent out dysmenorrhea in source has significant curative effect.
Theory of Chinese medical science is thought the pathogenesis of pain, for QI and blood obstructed, stagnation of QI and blood may bring about pain.With regard to dysmenorrhea, particularly important with the major physiological function of liver.Liver storing blood: the store blood function of liver, mainly be embodied in the liver and must store certain blood volume, the meaning of the liver department sea of blood with the yang-energy ascension of restriction liver, did not make highly, to safeguard the catharsis function of liver, made it to dash with bar and reached.Liver controlling conveyance and dispersion, catharsis are harmonizing the functional activities of vital QI, promote the important step of blood operation, and the effect of harmonizing emotions is arranged.The catharsis function is normal, then QI movement being in harmonious way, QI and blood and accent.Thereby, be conceived to the liver department sea of blood, main again catharsis, the irritability bar reaches, and then the sea of blood is logical transfers, and is we's theoretical foundation.
The side separates: Radix Salviae Miltiorrhizae is monarch drug tool stasis-dispelling and pain-killing in the side, promoting blood flow to regulate menstruation, the effect of the relieving restlessness that clears away heart-fire.Ingredient mainly contain liposoluble constituent TANSHINONES (I, IIA, IIB), iso tanshinone etc.; The water soluble ingredient danshensu, protocatechualdehyde etc.Pharmacological action shows these compositions to cardiovascular, and hemorheology and central nervous system have better effect.Ministerial drug in the Radix Paeoniae Alba side of being has the suppressing the hyperactive liver pain relieving, nourishing blood for regulating menstruation, astringing YIN to stop sweating effect.Ingredient peoniflorin and other glycosides, as oxypaeoniflorin, benzoylpaeoniflorin etc., the calmness of tool maincenter, analgesia, spasmolytic, protect the liver, antiinflammatory, anti-stress and regulate effect such as immunologic function.Especially act as the strongest with peoniflorin.Ministerial drug in the Rhizoma Cyperi side of being, tool promoting QI circulation for relieving depression, the effect of menstruction regulating and pain relieving.Ingredient has volatile oil, sugar, starch etc.Pharmacological action shows antiinflammatory, and is stable, antipyretic effect.Wherein volatile oil has estrogen-like effects, is the main component of treatment menoxenia.Ministerial drug in the Rhizoma Corydalis side of being, tool are invigorated blood circulation, are had a respite, the pain relieving effect.Ingredient mainly is an alkaloids, and pharmacological action shows that alkaloid has analgesia, calmness, effects such as anesthesia.Adjuvant drug in Fructus Foeniculi, the Fructus Toosendan side of being.Fructus Foeniculi tool dispersing cold for relieving pain, the regulating qi-flowing for harmonizing stomach effect.Ingredient has volatile oil, fatty oil, coumarin etc.Wherein volatile oil has estrogen-like effects.Fructus Toosendan tool soothing liver-QI, the promoting the circulation of QI to relieve pain effect.Ingredient has Toosendanin, violet incense ketoside, Fructus Toosendan lactone etc.Pharmacological action has effects such as antiinflammatory, antibiotic, function of gallbladder promoting, inhibition maincenter.Messenger drug in the Radix Glycyrrhizae side of being, the tool relieving spasm to stop pain, invigorating the spleen and replenishing QI, the coordinating the actions of various ingredients in a prescription effect, ingredient has triterpenes, flavonoid, polysaccharide etc.Pharmacological action has the effect of adrenocortical hormone sample, antiulcer, antiinflammatory etc.Seven medicines share, and bring out the best in each other, and the gas promoting the circulation of blood and the stasis of blood are dispelled, and vessels of the uterus is unobstructed, general rule not bitterly, dysmenorrhea is from ending.
Beneficial effect
Pharmacodynamics test research
This research intends observing medicine of the present invention to animal uterus smooth muscle contractile activity and electrical activity influence, and analgesia, calmness and antiinflammatory action.
Medicine medicine of the present invention, test does not contain the excipient extract powder with it, is made into 50%, 25% and 12.5% suspension, rat and mouse stomach 4g/kg, 2g/kg and 1g/kg with distilled water, (people's consumption is 12g/ day to 20 times, 10 times and 5 times of behaviour consumption, 0.2g/kg).The centrifugal back of suspension supernatant is used for the isolated uterine test.With the excipient dextrin as the negative control medicine.
Positive control drug: use as if the western pharmaceutical factory in YUEYUESHU KELI Henan product batch number 960512 usefulness distilled water are made into 50% suspension.
Oxytocin inj Shanghai Yongfeng pharmaceutical Co. Ltd product batch number 950802
Diethylstilbestrol injection Shanghai the 9th pharmaceutical factory's product batch number 950214
Pharmaceutical factory of prednisone sheet Shijiazhuang City Xinhua product batch number 951105
Pentobarbital sodium Shanghai biochemical reagents factory provides, and is made into 0.15% solution with distilled water: 9709009
Water-soluble Astra of aspirin (Wuxi) pharmaceutical Co. Ltd lot number: 960021
High molecular dextran Beijing Bang Ding Biomedicines, Inc. provides, and is made into 10% solution with distilled water.
Shanghai Research Institute of the TIANBAONING Chinese Academy of Sciences, Zhejiang Kang Enbei pharmaceutical Co. Ltd joint research and development lot number: 990111, be made into 0.2% suspension with distilled water and use.
Adrenalin hydrochloride injection 1mg/ml, Yongkang, Beijing pharmaceutical factory lot number: 990121-6.
Heparin 140u/mg, Beijing's bispin microbiological culture media products factory lot number: 980428.
Red blood cell deformation liquid Beijing Steellex Scientific Instrument Company provides lot number: 9910.
The powerful pharmaceutical factory in indometacin powder Shijiazhuang lot number: 900512, be made into 0.8% suspension with 0.5%CMC solution and use.
Anticoagulant EDTA-Na
2Being mixed with 2% solution with 0.9% normal saline uses.
PGE
2Medicine box Suzhou hospital produces (experimental implementation by specification), and 301 Hospital of the Chinese People's Liberation Army provides.
PGE
2The product Lot 71H3795 of sigma company
Animal rat Wistar kind, all female, 200～240 grams. available from zooscopy institute of Chinese Academy of Medical Sciences breeding farm, the certificate of competency: the moving word of doctor 01-3008 number.
Mice Kunming kind, all female, 18～22 grams, the isolated uterine test restrains with 28～30.Available from zooscopy institute of Chinese Academy of Medical Sciences breeding farm, the certificate of competency: the moving word of doctor 01-3001 number.
Rabbit, all female, 2.5～3.0 kilograms of body weight are available from animal supply station, suburb, Beijing.
Instrument two road electrophysiological recording instrument LMS-2B types, Chengdu Instruement Factory
Toy activity inventory instrument MK-ANIMAEX type japanese product
Analytical balance AEG-220 japanese product
Stereomicroscope XTL-1 type, Tyke, Beijing instrument company product
Refrigerated centrifuge labofuge 400R type, Germany makes
Red blood cell deformation/gathering tester LG-B-190 type, Beijing Steellex Scientific Instrument Company
Blood viscosity instrument R80 type, Beijing Steellex Scientific Instrument Company
γ microcomputer multiple tracks analyzer T-T-630G type, Beijing 261 factories
Ultrasonic cell disruptor JY92-II type, Ningbo new sesame instruments for scientific research institute
Refrigerated centrifuge DL-4000B type.Make in Shanghai
Method and result
Pharmacodynamic study requirement with reference to " study of tcm new drug guide " [1] relevant treatment dysmenorrhea Chinese medicine, intending observing medicine of the present invention reaches in the movable influence of body normal unpregnancy animal uterus is stripped, to the influence of clear-headed rat uterus electrical activity, and the antagonism that oxytocin is caused uteri excitation.Observe antiinflammatory, analgesia and the sedation of this medicine.
One, to the influence of normal mouse isolated uterine smooth muscle contractile activity and oxytocin effect
Method test is with totally 50 of Kunming kind female mices, divides totally 5 groups of the large, medium and small dosage group of medicine of the present invention, YUEYUESHU matched group and excipient matched groups.Low power microscope detects down mouse vagina secretions, and rutting period is based on keratinocyte, gets the rutting period mice and experimentizes.Take off cervical vertebra and put to death mice, open separating uterus surrounding tissue and blood vessel behind the abdomen, bilateral cornua uteri two ends are merged ligation, get the uterus section that is about 1.5cm and be suspended in the Magnus' bath that fills the 15ml krebs solution, logical medical oxygen, constant temperature is at 37.0 ± 0.5 ℃.The contraction movement of uterine smooth muscle is recorded on the two road electrophysiological recording instrument through tonotransducer, record uterus normal contraction activity 30 minutes, and nutritional solution is changed once in the centre.In bath, add 20%, 10% or 5% drug solution supernatant 0.15ml of the present invention, make the medicine final concentration in the bath be respectively 2 * 10
-3, 1 * 10
-3, 0.5 * 10
-3, observe the variation of administration front and back frequency of uterine contraction, amplitude and energy (frequency * amplitude), calculate its rate of change.Other gets 44 of mices, divides the heavy dose of group of medicine of the present invention, middle dosage group, YUEYUESHU matched group and excipient matched group, and isolated uterine preparation of specimen is the same.Add oxytocin 0.05ml in bath, spastic contraction appears in uterine smooth muscle immediately, and tension force obviously increases and form platform, adds different medicinal liquid 0.15ml after 2.5 minutes respectively, writes down the spastic contractive amplitude 50% needed time (t that descends
1/2).
Result of the test is organized a t check, compare with the excipient matched group, drug effect is with P＜0.05, and P＜0.01 is a significance.
Normal mouse isolated uterine smooth muscle contraction frequency is 1.3 ± 0.4 times/minute as a result, and amplitude is 2.1 ± 1.0 grams.Compare with excipient, medicine of the present invention and YUEYUESHU CHONGJI all have the effect of the uterine contraction of inhibition, and be wherein the strongest with the heavy dose of group effect of medicine of the present invention, shows certain dose-effect relationship.See Table 1-1 and Fig. 1-1.
Table 1-1 medicine of the present invention is to the influence of normal mouse isolated uterine smooth muscle contractile activity
| Group | Final concentration * 10 -3??g/ml | Number of animals only | Rate of change x ± s frequency and amplitude energy before and after the administration | ||
| The excipient contrast | ??2.0 | ??10 | ??-0.02±0.14 | ??0.16±0.36 | ??0.17±0.38 |
| Medicine of the present invention | ??2.0 | ??10 | ??-0.55±0.26 ** | ??-0.58±0.28 ** | ??-0.76±0.17 ** |
| Medicine of the present invention | ??1.0 | ??10 | ??-0.50±0.12 ** | ??-0.48±0.19 ** | ??-0.75±0.08 ** |
| Medicine of the present invention | ??0.5 | ??10 | ??-0.31±0.15 ** | ??-0.26±0.12 ** | ??-0.49±0.14 ** |
| YUEYUESHU KELI | ??2.0 | ??10 | ??-0.35±0.19 ** | ??-0.42±0.23 ** | ??-0.60±0.19 ** |
Annotate: compare with the excipient matched group,
*P＜0.01
Drip oxytocin in the bath and can make uterine smooth muscle occur spastic contraction immediately, tension force obviously increases, and forms platform, and its backward pull descends gradually, and transfers a phasic property contraction to.Compare with the excipient matched group, big or middle dosage group of medicine of the present invention and YUEYUESHU administration group all can obviously shorten tension force decline t
1/2Time, the heavy dose of group effect of medicine wherein of the present invention is the most remarkable, and with the YUEYUESHU CHONGJI group comparison of same dose, inhibitory action obviously strengthens (P＜0.01), sees Table 1-2, Fig. 1-2.
Table 1-2 agents alleviate oxytocin of the present invention causes the effect of Mouse Uterus smooth muscle spasm
| Group | Number of animals (only) | T1/2 (second) x ± s |
| Excipient contrast 2 * 10 -3g/ml | ??10 | ??91.60±36.86 |
| Medicine heavy dose 2 * 10 of the present invention -3g/ml | ??10 | ??24.20±17.37 **★★ |
| Dosage 1 * 10 in the medicine of the present invention -3g/ml | ??10 | ??40.80±32.47 ** |
| YUEYUESHU contrast 2 * 10 -3g/ml | ??14 | ??62.43±31.34 * |
Annotate: compare with the excipient matched group,
*P＜0.05,
*Compare with YUEYUESHU P＜0.01, ★ ★ P＜0.01
Two, to the influence of rabbit at the body uterine contraction activity
18 of Female rabbits of method test, 2.5～3.0 kilograms of body weight.Divide dosage group (2g/kg), medicine small dose group of the present invention (1g/kg) and positive control drug YUEYUESHU group (4g/kg) in excipient matched group (4g/kg), the heavy dose of group of medicine of the present invention (4g/kg), the medicine of the present invention.Rabbit is anaesthetized with urethane, the 1g/kg intravenous injection.After the anesthesia that rabbit back of the body position is fixing, open abdomen and expose the uterus, separate about 3 centimeter length uterus, two ends are fixed, and adopt suspension method to be recorded in the contraction movement in palace, seat.The contraction movement in uterus is recorded on the two road electrophysiological recording instrument through tonotransducer.The uterus tension load is 2g.Record uterine contraction activity 30～40 minutes, through being embedded in the intubate administration of 12 rectum in advance, used drug level 50%, 25% and 12.5%, medication volume are 8ml/kg then.Uterine contraction activity in 90 minutes is observed contractive amplitude after the record administration, the variation of contraction frequency, and calculate uterine motility (amplitude * frequency).With uterine contraction activity in preceding 20 minutes of the administration is contrast, observes drug effect, organizes a t check, is that drug effect has the significance meaning with p＜0.05 and p＜0.01.
Heavy dose of group of medicine of the present invention as a result and middle dosage group have significant inhibitory effect to the rabbit frequency of uterine contraction, and a certain amount of effect relationship is arranged.The heavy dose of group of medicine of the present invention has remarkable inhibitory action to the contractive amplitude in uterus, but not as remarkable to the inhibitory action of frequency.The big or middle dosage group of medicine of the present invention also has remarkable inhibitory action to uterine motility.Contrast medicine YUEYUESHU also has obvious inhibitory action (table 2) to uterine contraction activity.
Table 2-1 medicine of the present invention is to rabbit frequency of uterine contraction influence on the throne
| Group | Dosage | Number of animals (only) | Before the administration | Contraction frequency (10 times/minute) 10-30 | (branch) 40-60 after X ± S administration | ??70--90 |
| Vehicle group | ??4g/kg?i.d | ??6 | 0.83 ± 0.24 (rate of change) | ??0.80±0.15 ??-0.02±0.11 | ??0.84±0.25 ??0.02±0.22 | ??0.85±0.26 ??0.01±0.18 |
| The heavy dose of group of medicine of the present invention | ??4g/kg?i.d | ??7 | 1.03 ± 0.28 (rate of change) | ??0.76±0.10 Δ??-0.23±0.18 * | ??0.61±0.19 ΔΔ??-0.38±0.22 ** | ??0.74±0.26 ??-0.27±0.21 * |
| Dosage group in the medicine of the present invention | ??2g/kg?i.d | ??7 | 0.97 ± 0.33 (rate of change) | ??0.74±0.18 ??-0.16±0.31 | ??0.69±0.15 Δ??-0.22±0.19 | ??0.64±0.19 Δ??-0.30±0.07 ** |
| Medicine small dose group of the present invention | ??1g/kg?i.d | ??7 | 0.62 ± 0.32 (rate of change) | ??0.71±0.22 ??0.09±0.29 | ??0.59±0.21 ??0.00±0.29 | ??0.59±0.21 ??0.00±0.28 |
| The YUEYUESHU KELI group | ??4g/kg?i.d | ??6 | 0.75 ± 0.26 (rate of change) | ??0.64±0.14 ??0.00±0.27 | ??0.59±0.22 ??-0.19±0.21 | ??0.56±0.26 ??-0.27±0.10 * |
Annotate: compare with vehicle group
*P＜0.05
*P＜0.01 is with comparison Δ p＜0.05 Δ Δ p＜0.01 before the administration
Table 2-2 medicine of the present invention is to rabbit uterine contraction amplitude influence on the throne
| Group | Dosage | Number of animals (only) | Before the administration | Contractive amplitude (g) 10--30 | (branch) 40--60 after X ± S administration | ??70--90 |
| Vehicle group | ??4g/kg?i.d | ??6 | 2.64 ± 0.64 (rate of change) | ??2.64±0.8 ??-0.01±0.15 | ??2.86±0.54 ??0.00±0.13 | ??3.24±0.92 ??0.06±0.14 |
| The heavy dose of group of medicine of the present invention | ??4g/kg?i.d | ??7 | 2.28 ± 0.77 (rate of change) | ??2.12±0.58 ??-0.04±0.10 | ??1.89±0.78 ??-0.16±0.18 | ??1.64±1.05 ??-0.28±0.32 * |
| Dosage group in the medicine of the present invention | ??2g/kg?i.d | ??7 | 1.36 ± 0.38 (rate of change) | ??1.53±0.50 ??0.13±0.19 | ??1.53±0.64 ??0.14±0.28 | ??1.39±0.62 ??0.03±0.32 |
| Medicine small dose group of the present invention | ??1g/kg?i.d | ??7 | 1.90 ± 0.96 (rate of change) | ??1.96±1.03 ??0.03±0.21 | ??1.89±1.34 ??-0.03±0.39 | ??1.88±1.58 ??-0.08±0.48 |
| YUEYUESHU KELI | ??4g/kg?i.d | ??6 | 1.27 ± 0.48 (rate of change) | ??1.04±0.32 ??-0.19±0.18 | ??1.12±0.32 ??-0.09±0.11 | ??1.11±0.36 ??-0.17±0.14 * |
Annotate: compare with vehicle group
*P＜0.05
*P＜0.01
With comparison Δ p＜0.05 Δ Δ p＜0.01 before the administration
Table 2-3 medicine of the present invention is to rabbit uterine motility influence on the throne
| Group | Dosage | Number of animals (only) | Before the administration | Energy 10-30 | (branch) 40-60 after X ± S administration | ??70-90 |
| Vehicle group | ??4g/kg?i.d | ??6 | 2.16 ± 0.68 (rate of change) | ??2.14±0.92 ??0.02±0.11 | ??2.12±0.46 ??-0.04±0.24 | ??2.15±0.74 ??0.02±0.20 |
| The heavy dose of group of medicine of the present invention | ??4g/kg?i.d | ??7 | 2.19 ± 0.39 (rate of change) | ??1.58±0.34 Δ??-0.27±0.14 ** | ??1.19±0.60 Δ??-0.48±0.22 ** | ??1.26±0.78 Δ??-0.41±0.33 * |
| Dosage group in the medicine of the present invention | ??2g/kg?i.d | ??7 | 1.32 ± 0.58 (rate of change) | ??1.11±0.33 ??-0.07±0.29 | ??1.08±0.52 ??-0.17±0.14 | ??0.89±0.52 ??-0.30±0.25 * |
| Medicine small dose group of the present invention | ??1g/kg?i.d | ??7 | 1.18 ± 0.80 (rate of change) | ??1.35±0.87 ??0.18±0.55 | ??1.07±0.75 ??-0.05±0.22 | ??1.31±1.32 ??-0.09±0.40 |
| The YUEYUESHU KELI group | ??4g/kg?i.d | ??6 | 0.99 ± 0.68 (rate of change) | ??0.65±0.32 ??-0.28±0.22 * | ??0.62±0.11 ??-0.24±0.26 | ??0.64±0.45 ??-0.36±0.09 * |
Annotate: compare with vehicle group
*P＜0.05
*P＜0.01
With comparison Δ p＜0.05 Δ Δ p＜0.01 before the administration
Three, to the influence of clear-headed rat uterus smooth muscle normal electrical activity and oxytocin effect
The method experiment divides 4 groups, the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), YUEYUESHU matched group (4g/kg), excipient matched group (5g/kg).Rat opens abdomen under pentobarbital sodium (30mg/kg, lumbar injection) anesthesia, in pipe stage casing, an Aconitum carmichaeli Debx. palace, and the bipolar silver wire electrode of heeling-in, lead passes external and fixing through skin of back, close abdomen.Rat post-operative recovery 3～5 days.Select the transvaginal plate coating checking, be defined as estrous rat (the same mice of method) and experimentize.Rat is put into the Mus box; nape portion lead is connected to two road electrophysiological recording instrument; trace the normal uterus electrical activity; time constant is 0.02; High frequency filter is 10HZ; chart speed is 1mm/ second. the record normal activity was irritated the tested medicine of stomach after 30～40 minutes, uterine electrical activity frequency, amplitude and the variation of burst discharge persistent period in 40 minutes after the observation administration.
In addition with rutting period rat trace the uterus normal electrical activity after 30～40 minutes, intramuscular injection oxytocin 0.2u/ only gives oxytocin after 5 minutes, irritates the tested medicine of stomach, observes the influence of various medicines to oxytocin excited uterus effect.
Experimental result is represented with the rate of change of frequency, amplitude and the persistent period of uterus bunch shape electrical activity before and after the administration, compares with the excipient matched group, and t check through between group, with P＜0.05, P＜0.01 is the drug effect significance.
This experimental record is to being in estrous normal waking state rat as a result, and uterine electrical activity is a bunch shape granting, and frequency is 1.1 ± 0.5 times/minute, every bunch of discharge sustain 7.5 ± 4.5 seconds, and amplitude is 418.4 ± 212.7 μ v (n=11).Same rat uterus electrical activity rule is constant substantially in different rutting period, but interindividual variation is bigger.With the effect of excipient matched group relatively, the heavy dose of group of medicine of the present invention (4g/kg) the burst discharge frequency that can obviously slow down acts on sustainable more than 40 minutes.Dosage group (2kg) only showed certain inhibitory action in 40 minutes in the medicine of the present invention after administration.The YUEYUESHU matched group does not have a significant effect to uterine electrical activity.Various medicines all do not have obvious influence to the amplitude and the persistent period of burst discharge.See Table 3-1, table 3-2, table 3-3, Fig. 3-1, Fig. 3-2, Fig. 3-3 and Fig. 3-4.
Table 3-1 medicine of the present invention is to the influence of normal clear-headed rat uterus burst discharge frequency
| Group | Number of animals (only) | Burst discharge frequency change rate x ± s after the administration | ||
| 0～10 minute | 20～30 minutes | 30～40 minutes | ||
| Figuration contrast 5g/kg | ??10 | ??0.05±0.13 | ??-0.41±0.28 | ??0.01±0.20 |
| Medicine 4g/kg of the present invention | ??10 | ??-0.25±0.29 ** | ??-0.41±0.16 ** | ??-0.42±0.18 ** |
| Medicine 2g/kg of the present invention | ??10 | ??-0.14±0.32 | ??-0.15±0.31 | ??-0.27±0.30 * |
| YUEYUESHU KELI 4g/kg | ??10 | ??0.04±0.14 | ??-0.15±0.15 | ??-0.14±0.25 |
Annotate: compare with the excipient matched group,
*P＜0.05,
*P＜0.01
Table 3-2 medicine of the present invention is to normal clear-headed rat uterus burst discharge effect on amplitude
| Group | Number of animals (only) | Burst discharge amplitude change rate x ± s after the administration | ||
| 0～10 minute | 20～30 minutes | 30～40 minutes | ||
| Figuration contrast 4g/kg | ??10 | ??0.03±0.22 | ??0.07±0.19 | ??0.07±0.18 |
| Medicine 4g/kg of the present invention | ??10 | ??0.16±0.22 | ??-0.07±0.22 | ??-0.12±0.16 |
| Medicine 2g/kg of the present invention | ??10 | ??-0.02±0.18 | ??-0.22±0.31 | ??0.05±0.25 |
| YUEYUESHU KELI 4g/kg | ??10 | ??0.06±0.26 | ??-0.07±0.23 | ??-0.05±0.14 |
Table 3-3 medicine of the present invention is to the influence of normal clear-headed rat uterus burst discharge persistent period
| Group | Number of animals (only) | Burst discharge persistent period rate of change x ± s after the administration | ||
| 0～10 minute | 10～20 minutes | 30～40 minutes | ||
| Excipient contrast 4g/kg | ??10 | ??0.04±0.23 | ??-0.04±0.19 | ??0.07±0.15 |
| Medicine 4g/kg of the present invention | ??10 | ??0.10±0.27 | ??0.12±0.37 | ??0.03±0.43 |
| Medicine 2g/kg of the present invention | ??10 | ??-0.17±0.23 | ??-0.11±0.26 | ??-0.14±0.15 |
| YUEYUESHU KELI 4g/kg | ??10 | ??0.09±0.12 | ??0.01±0.34 | ??-0.10±0.26 |
Behind rat intramuscular injection oxytocin in the rutting period 0.2u/kg, electrical activity obviously strengthens.0.83 ± 0.20 time/minute before by administration of burst discharge frequency is increased to 1.58 ± 0.26 times/minute, and effect is (P＜0.01) significantly.492.4 ± 208.4 μ Vs of burst discharge amplitude before by administration are increased to 558.5 ± 280.0 μ V, and 7.5 ± 4.5 seconds before by administration of power generation continuous time of bunch shape are increased to 10.0 ± 4.5 seconds, but there are no significant on statistics difference (P＞0.05).To 5 minutes filling stomach different pharmaceuticals after the oxytocin, excipient and each administration group all have inhibitory action to the uterus discharge frequency increase that oxytocin causes, the acting duration of prompting oxytocin is shorter, the trend that has nature to recover, but compare with vehicle group, the heavy dose of group of medicine of the present invention inhibitory action more obvious (P＜0.01), acting duration reached more than 40 minutes.Each medicine does not all have obvious influence to burst discharge amplitude and persistent period, sees Table 3-4, Fig. 3-5,6,7,8.
Table 3-4 medicine of the present invention causes the influence that clear-headed rat uterus burst discharge frequency increases to oxytocin
| Group | Number of animals (only) | Burst discharge frequency (inferior/minute) (rate of change) x ± s gives after the oxytocin 0～10 minute 20～30 minutes 30～40 minutes |
| Excipient contrast 4g/kg | ??10 | 1.72±0.63???1.40±0.19???????1.22±0.17?????1.12±0.28 ????????????(-0.18±0.12)???(-0.26±0.11)???(-0.27±0.12) |
| Medicine 4g/kg of the present invention | ??10 | 1.61±0.30???1.29±0.26???????0.90±0.17 **???0.80±0.20 *????????????(-0.26±0.11)???(-0.48±0.13)???(-0.50±0.13) |
| Medicine 2g/kg of the present invention | ??10 | 1.68±0.52???1.02±0.54???????1.12±0.48??????1.05±0.41 ????????????(-0.16±0.20)???(-0.34±0.13)???(-0.38±0.16) |
| YUEYUESHU KELI 4g/kg | ??10 | 1.66±0.34???1.20±0.47???????1.04±0.36??????1.10±0.20 ????????????(-0.08±0.12)???(-0.30±0.14)???(-0.37±0.18) |
Annotate: compare with the excipient matched group,
*P＜0.05,
*P＜0.01
Four, analgesic activity
1, mice oxytocin writhing method
The method test female mice, body weight 18～22 grams, totally 84, be divided into 6 groups, i.e. excipient matched group, medicine 4g/kg of the present invention group, medicine 2g/kg of the present invention group, medicine 1g/kg of the present invention group, YUEYUESHU matched group 4g/kg, atropine matched group 2mg/kg.Mouse peritoneal injection stilbestrol 0.4mg/ only, successive administration 3 days, behind the tested medicine of mouse stomach on the 4th 1 hour, lumbar injection oxytocin 1u/ only, the incubation period that body occurs turned round in record, and what occur in 0～10 minute and 10～20 minutes after the administration turns round body number of times, the relatively difference between administration group and the excipient matched group, organizing a t check, is that drug effect has significant difference with p＜0.05 and p＜0.01.
The writhing response of vehicle group oxytocin as a result incidence rate is 83%, and medicine 4g/kg of the present invention and 2g/kg group all can obviously reduce turns round the body incidence rate, is respectively 71% and 77%, and other groups change not obvious.Medicine 2g/kg of the present invention and 1g/kg group is turned round body time number average obvious inhibitory action is arranged turning round in body incubation period and 10 minutes, and certain dose-effect relationship is arranged.The heavy dose of group of medicine of the present invention can obviously suppress to turn round in 0～10 minute the body number of times, but to there not being obvious influence incubation period.Contrast medicine YUEYUESHU does not have obvious effect, but atropine reduces mouse writhing number of times effect significantly (table 4-1).
Table 4-1 medicine of the present invention causes that to oxytocin mice reacts influence bitterly
| Grouping | Dosage | Number of animals (only) | Turn round body incubation period (second) | Turn round body number of times (inferior/10 minute) 0-10 branch | X ± S 10-20 branch |
| Excipient | ??4g/kg?p.o | ??14 | 71.6 ± 59.9 (incidence rates) | ??22.9±9.3 ??83％ | ??7.9±8.6 |
| Medicine of the present invention | ??4g/kg?p.o | ??14 | 64.7 ± 43.4 (incidence rates) | ??13.2±6.8 **??71％ | ??4.0±2.1 |
| Medicine of the present invention | ??2g/kg?p.o | ??13 | ??241.7±60.7 **(incidence rate) | ??7.8±4.9 **??77％ | ??5.2±2.9 |
| Medicine of the present invention | ??1g/kg?p.o | ??16 | ??133.8±76.0 *(incidence rate) | ??15.2±8.0 *??83％ | ??4.4±3.5 |
| YUEYUESHU KELI | ??4g/kg?p.o | ??12 | 97.6 ± 68.5 (incidence rates) | ??20.1±9.4 ??83％ | ??4.6±4.2 |
| Atropine | ??2mg/kg?i.p | ??13 | 72.3 ± 45.5 (incidence rates) | ??12.0±5.8 **??92％ | ??2.9±3.0 * |
Annotate: with excipient matched group ratio
*P＜0.05
*P＜0.01
2, mice acetic acid twisting method
The method experiment divides 4 groups, the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), YUEYUESHU matched group (4g/kg), excipient matched group (4g/kg).After the mouse stomach administration 1 hour, lumbar injection 0.6% acetum 0.1ml/10g body weight, was turned round the body number of times in 0～10 minute, 20～30 minutes at the incubation period that the record mouse writhing occurs.Relatively the difference between administration group and excipient matched group is checked through t, and P＜0.05 and P＜0.01 is the effect significance.
Medicine of the present invention as a result has obvious analgesic activity, can prolong mice and the body time (incubation period) occur turning round, reduces and turns round the body number of times, and effect continued more than 30 minutes, and was dose-effect relationship.(table 4-2)
Table 4-2 medicine Dichlorodiphenyl Acetate of the present invention causes the influence of mouse writhing reaction
| Group | Dosage (g/kg) | Number of animals (only) | (X ± S) (second) incubation period | Turned round body number of times (X ± S) (inferior/10 minute) 0～10 minute 20～30 minutes |
| The excipient contrast | ??4 | ??12 | ??176±17 | ??24.7±5.8??????39.9±3.5 |
| Medicine of the present invention | ??4 | ??12 | ??387±36 ** | ??9.7±2.2 **?????24.8±3.9 ** |
| Medicine of the present invention | ??2 | ??12 | ??209±13 ** | ??17.6±1.5 **????33.7±2.3 ** |
| YUEYUESHU KELI | ??4 | ??12 | ??466±18 ** | ??5.2±2.3 **?????17.9±6.3 ** |
Annotate: compare with the excipient matched group,
*P＜0.01
3, medicine of the present invention is to PGE
2Cause the influence of mouse writhing reaction
Method: get 60 of Kunming kind female mices, body weight 18.1 ± 1.0 grams, be divided into 5 groups, ordinary water matched group (10ml/kg), the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), small dose group (1g/kg), YUEYUESHU positive controls (4g/kg).Every day gastric infusion once, continuous 3 days, after the last administration 1 hour, every mouse peritoneal injection PGE
22.5mg/kg (0.1%, 0.25ml/10g), timing is immediately observed and body incubation period appears turning round in record, 0-30 divides and 30-60 divides mouse writhing number of times in two time periods.Calculate every group and turn round body generation percentage rate.Relatively between the administration group with the difference of ordinary water matched group, adopt T check and X 2 test respectively, serve as to act on significance with P＜0.05 and P＜0.01.
Result: PGE
2Be 10.85 minutes incubation period that causes the mouse writhing reaction, turns round body generation percentage rate and reach 75.0%.The heavy dose of group of medicine of the present invention, middle dosage group all have significant inhibitory effect, can obviously reduce and turn round the percentage rate that body takes place, and make and turn round the minimizing of body number of times, but small dose group does not have obvious effect.YUEYUESHU KELI also has the obvious suppression effect.See Table 4-3
Table 4-3 medicine of the present invention is to PGE
2Cause the influence of mouse writhing reaction
| Group | Dosage (g/kg) | Number of animals (only) | Incubation period (branch) | Turned round the body number of times 0～30 minute 30～60 minutes | Turn round the body percentage rate |
| The ordinary water matched group | ??4.0ml/kg ??p.0 | ??20 | ??10.85±8.55 ??(n＝15) | ??2.43±2.06????4.25±2.30 ??(n＝14)??????????(n＝4) | ??75％ |
| Medicine of the present invention | ??4.0?p.0 | ??10 | ??0.00％ ** | ||
| Medicine of the present invention | ??2.0?p.0 | ??10 | ??31.00±0.00 ??(n＝1) | ?????????1.00±0.00 ???????????(n＝1) | ??10.0％ ** |
| Medicine of the present invention | ??1.0?p.0 | ??10 | ??20.28±16.51 ??(n＝4) | ??1.33±0.58????2.00±1.00 ??(n＝3)???????????(n＝3) | ??40.0％ |
| YUEYUESHU KELI | ??4.0?p.0 | ??10 | ??0.00％ ** |
Annotate: compare with the ordinary water contrast,
*P＜0.01
Five, sedation
The method laboratory mice divides 4 groups, the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), YUEYUESHU matched group (4g/kg), excipient matched group.After the mouse stomach administration 1 hour, put it in the toy autonomic activities monitor active box, adapt to after 2 minutes, write down the movable number of times in 5 minutes.Relatively the difference between administration group and matched group is checked through t, and P＜0.05 and P＜0.01 is the effect significance.
Medicine 4g/kg of the present invention as a result irritates stomach, has certain sedation, and the mice autonomic activities is reduced, but the 2g/kg group does not have the obvious suppression effect.YUEYUESHU 4g/kg also can obviously suppress the autonomic activities of mice.(table 5-1)
Table 5-1. medicine of the present invention is to the influence of mice autonomic activities
| Group | Dosage (g/kg) | Number of animals (only) | Autonomic activities number of times X ± S | Movable suppression ratio (%) |
| The excipient contrast | ??4?P.0 | ??12 | ??713.3±22.5 | |
| Medicine of the present invention | ??4?P.0 | ??12 | ??689.4±30.8 * | ??3.35±0.18 |
| Medicine of the present invention | ??2?P.0 | ??12 | ??696.7±30.1 | ??2.33±0.11 |
| YUEYUESHU | ??4?P.0 | ??12 | ??663.3±62.5 * | ??7.01±0.07 |
Annotate: with excipient matched group ratio,
*P＜0.05,
Method (two): test is with 50 of Kunming mouses, and is female, 18.4 ± 1.1g.Test is divided into the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), small dose group (1g/kg) YUEYUESHU matched group (4g/kg), ordinary water matched group.Determine the subliminal hypnosis amount 24mg/kg of pentobarbital sodium through preliminary experiment, the mouse stomach administration is after 1 hour, the pentobarbital sodium of lumbar injection subliminal hypnosis dosage.The mice that continues more than 1 minute with righting reflex loss is the appearance sleep.Observe each group appearance sleep number of mice in 30 minutes, relatively the difference of administration group and the effect of ordinary water matched group adopts X 2 test, serves as the effect significance with P＜0.05 and P＜0.01.See Table 5-2.
The result: the heavy dose of group of medicine of the present invention has significant pentobarbital sodium synergism with middle dosage group, and the number of mice that sleep occurs significantly increases, and small dose group does not have obvious effect.The effect of three dosage groups is certain dose-effect relationship.See Table 5-2.
Table 5-2 medicine of the present invention is to the synergism of pentobarbital sodium
| Group | Dosage (g/kg) | Number of animals (only) | Sleep number of mice (only) | Sleep mice percentage rate % |
| The ordinary water matched group | ??10ml/kg?p.0 | ??10 | ??0 | ??0 |
| Medicine of the present invention | ??4.0?p.0 | ??10 | ??6 | ??60 ** |
| Medicine of the present invention | ??2.0?p.0 | ??10 | ??4 | ??40 ** |
| Medicine of the present invention | ??1.0?p.0 | ??10 | ??1 | ??10 |
| YUEYUESHU KELI | ??4.0?p.0 | ??10 | ??0 | ??0 |
Annotate: compare with the ordinary water contrast
*P＜0.01
Six, antiinflammatory action
Method adopts dimethylbenzene to bring out the mice ear method, observes the antiinflammatory action of medicine of the present invention.Experiment divides 5 groups, the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), YUEYUESHU matched group (4g/kg), excipient matched group, prednisone matched group (0.4mg/kg).The continuous gastric infusion of mice 4 days, after the last administration 1 hour, dimethylbenzene is evenly spread upon two sides before and after the auris dextra, left ear is contrast.Behind the coating 1 hour, take off cervical vertebra and put to death mice, cut left and right sides ear, sweep away the auricle of two ear same area with 7mm diameter card punch, weigh respectively. with two auricle weight differences is the ear swelling degree, and the swelling degree is the ear swelling rate with the ratio of left ear weight.Relatively the difference between administration group and the excipient matched group is checked through t, and P＜0.05 and P＜0.01 is the effect significance.
The continuous gastric infusion of result 4 days, the mice ear that the big or middle dosage group of medicine of the present invention causes dimethylbenzene alleviates, and the swelling rate descends, heavy dose of group of effect more remarkable (P＜0.01).Positive control drug YUEYUESHU, prednisone group also have significant antiinflammatory action.(seeing Table 6)
Table 6 medicine xylol of the present invention brings out the influence of mice ear
| Group | Dosage (g/kg) | Number of animals (only) | Swelling degree X ± S | Swelling rate X ± S |
| The excipient contrast | ??4????????P.0 | ??12 | ??6.6±2.7 | ??64.08±19.55 |
| Medicine of the present invention | ??4????????P.0 | ??12 | ??4.3±2.4 | ??39.15±12.15 ** |
| Medicine of the present invention | ??2????????P.0 | ??12 | ??4.7±2.4 | ??41.43±27.77 * |
| YUEYUESHU | ??4????????P.0 | ??12 | ??4.6±2.1 | ??41.59±14.61 ** |
| Prednisone | ??0.4mg/kg?P.0 | ??12 | ??3.5±1.1 | ??39.31±13.65 ** |
Annotate: compare with the excipient matched group,
*P＜0.05,
*P＜0.01
Seven, medicine of the present invention is to the influence of the childhood rat uterus and the development of ovary and estrogen
40 of female rats of method test, body weight 45-55g, divide excipient matched group (4g/kg), the heavy dose of group of medicine of the present invention (4g/kg), dosage group (2g/kg) in the medicine of the present invention, medicine small dose group of the present invention (1g/kg), gastric infusion is after 2 weeks continuously, rat is weighed, with the liquor-saturated 40mg/kg of pentobarbital sodium, fixedly rear neck artery is got blood, places centrifugal after half day, 3000rpm, 10 minutes, get serum, measure serum estradiol and progesterone content (estradiol radioimmunology analysis medicine box and progesterone radioimmunology analysis medicine box to put the method for exempting from, provide product batch number 9812 by the Fu Rui of Beijing bio-engineering corporation).Open rat abdominal cavity, pluck uterus and ovary, weigh, calculate organ index, i.e. uterus (ovary) weight/body weight.
Medicine of the present invention does not as a result have obvious influence to the childhood rat uterus and the development of ovary, and serum estrogen and progesterone level are not seen obvious influence (table 7) yet.
Table 7. medicine of the present invention is to the influence of childhood rat sexual organ and hormonal readiness
| Group | Dosage | Number of animals (only) | Organ index (mg/g) x ± s | Gonadal hormone x ± s | ||
| Ovary | The uterus | Estradiol (pg/ml) | Progesterone (ng/ml) | |||
| Vehicle group | ??4g/kg?p.o | ??10 | ??0.39±0.08 | ??1.88±0.43 | ??17.24±5.93 | ??1.78±0.50 |
| Medicine of the present invention | ??4g/kg?p.o | ??10 | ??0.39±0.06 | ??1.63±0.64 | ??15.65±5.02 | ??1.65±0.73 |
| Medicine of the present invention | ??2g/kg?p.o | ??10 | ??0.39±0.06 | ??1.33±0.30 | ??14.71±4.30 | ??1.31±0.13 |
| Medicine of the present invention | ??1gkg?p.o | ??9 | ??0.41±0.07 | ??157±0.18 | ??16.99±3.42 | ??1.65±0.57 |
Eight, medicine of the present invention is to the microcirculatory influence of mice mesentery blood vessel
Method: list of references
[2]Get 72 of Kunming mouses, female, 19.7 ± 0.8g is divided into 6 groups: the heavy dose of group of medicine of the present invention (4g/kg), dosage group (2g/kg) in the medicine of the present invention, medicine small dose group of the present invention (1g/kg), ordinary water blank group (10ml/kg), model control group (10ml/kg), bamyl (aspirin) matched group (5mg/kg).Mouse stomach is administered once every day, successive administration five days.Five groups of mices of except that ordinary water blank group all the other are all in last administration tail vein injection 10% dextran after a hour.Mice is used chloral hydrate anesthesia, do a longitudinal cut, expose ileocecus, observe microcirculation on the ileocecus 1.5cm place ileum wall down in Stereo microscope (2.5 times) in the mice right lower abdomen.Observation index is the erythrocyte fluidised form 1.: the erythrocyte fluidised form is divided into level Four, and 0 grade is straight line (line grain) shape; The I level is empty (grain) wire; The II level is grain (wadding) shape; The III level is the stasis shape, and no erythrocyte flows through in the blood capillary.2. point of intersect of the capillary network number: observe and the record high molecular dextran after when 5 minutes and 10 minutes microcirculation change, the difference of administration group and matched group relatively, result of the test is checked through t, P＜0.05 and P＜0.01 is for acting on significance.
The result: behind the injected in mice high molecular dextran, microcirculation disturbance appears in the ileum blood vessel, and each dosage group of erythrocytic granule all can obviously be improved the erythrocyte fluidised form, and heavy dose of group can also increase the blood capillary net number.Above presentation of results medicine energy of the present invention microcirculation improvement obstacle, the most remarkable with the heavy dose group.See Table 8.
Table 8 medicine of the present invention is to the microcirculatory influence of mice ileum
| Group | Dosage g/kg p.0 | Number of animals N | Erythrocyte fluidised form progression | The blood capillary net number | ||
| 5 minutes | 10 minutes | 5 minutes | 10 minutes | |||
| The blank group | ??10g/kg | ??12 | ??0.00±0.00 | ??0.00±0.00 | ??8.75±1.22 | ??8.75±1.22 |
| Model control group | ??4.0 | ??15 | ??1.87±0.35# | ??#2.47±0.52## | ??7.80±1.82 | ??6.07±1.58## |
| Medicine of the present invention | ??4.0 | ??12 | ??1.25±0.45 ** | ? *1.42±0.51 * | ??8.67±1.37 | ??8.17±1.40 ** |
| Medicine of the present invention | ??2.0 | ??11 | ??1.73±0.79 | ??2.09±0.70 | ??7.64±1.69 | ??6.27±1.90 |
| Medicine of the present invention | ??1.0 | ??11 | ??1.64±0.67 | ??1.91±0.54 * | ??8.55±1.13 | ??6.82±2.18 |
| The bamyl (aspirin) matched group | ??0.005 | ??11 | ??1.36±0.50 * | ? *1.82±0.87 * | ??8.09±2.07 | ??6.55±2.66 |
Annotate: with blank group ratio, ##P＜0.01; With the model control group ratio
*P＜0.05,
*P＜0.01
Nine, medicine of the present invention is to the influence of acute stress hemorheology of rat
Method: list of references
[4,3], rat, the Wistar kind, female, body weight 200.9 ± 6.8g.Test is divided into 6 groups: ordinary water blank group (10ml/kg), model control group (10ml/kg), the heavy dose of group of medicine of the present invention (4g/kg), middle dosage group (2g/kg), small dose group (1g/kg), TIANBAONING positive controls (20mg/kg).Each treated animal gastric infusion every day 2 times, successive administration 5 times, modeling after the last administration.Except that ordinary water blank group, all the other mouse subcutaneous injection epinephrine 1mg/kg were placed in the water-bath (8 ℃ of water temperatures) in 2 hours and soaked 5 minutes, injected epinephrine 1mg/kg once more after 2 hours.Give for the first time behind the epinephrine 24 hours, (pentobarbital sodium 35mg/kg, ip) the total arterial blood drawing 5ml of collare put into the test tube of heparinization to rat anesthesia immediately, shake up gently.Get hematometry red cell deformability, aggregation respectively, and whole blood and plasma viscosity, hematocrit value.
The result: acute stress rat blood rheological characteristic generation significant change, red cell deformability weakens, and aggregation obviously strengthens; Whole blood viscosity and plasma viscosity raise.Medicine of the present invention can obviously increase the erythrocytic morphotropism of acute stress rat, but its aggregation is not had obvious influence, sees Table 2.Medicine of the present invention also can obviously reduce under the acute stress rat low shear rate (5S-1,1S-1) whole blood viscosity, but to (200S-1,30S-1) whole blood viscosity does not have obvious influence under the high shear rate.Medicine of the present invention also has the reduction effect to the plasma viscosity of acute stress rat.Medicine of the present invention does not have obvious influence to hematocrit value.
Table 9-1 medicine of the present invention is to acute stress rat red cell deformability, the influence of aggregation
| Group | Dosage g/kg | Number of animals | Morphotropism | Aggregation | ||
| The maximum distortion index | Area under curve | The maximum distortion index | Area under curve | |||
| The blank group | ??10 | ??0.66±0.03 | ??311.83±19.77 | ??0.43±0.09 | ??76.111±16.71 | |
| Model control group | ??11 | ??0.62±0.05# | ??277.85±25.42# | ??0.66±0.10## | ??136.04±20.18## | |
| The TIANBAONING matched group | ??0.02 | ??10 | ??0.67±0.04 * | ??306.25±20.85 * | ??0.58±0.10 * | ??120.53±22.06 * |
| Medicine of the present invention | ??4.0 | ??10 | ??0.68±0.03 ** | ??317.35±18.70 ** | ??0.78±0.18 | ??154.55±37.32 |
| Medicine of the present invention | ??2.0 | ??10 | ??0.69±0.04 ** | ??328.53±27.26 ** | ??0.64±0.08 | ??129.82±14.93 |
| Medicine of the present invention | ??1.0 | ??10 | ??0.70±0.07 * | ??332.33±47.33 ** | ??0.67±0.16 | ??134.77±28.56 |
Compare with the blank group: compare with model group #P＜0.05 ##P＜0.01:
*P＜0.05
*P＜0.01
Table 9-2 medicine of the present invention is to the influence of acute stress rat whole blood and blood plasma viscosity and hematocrit value
| Group | Dosage (g/k g) | Number of animals | Whole blood viscosity | Hematocrit value % | Plasma viscosity 100S -1 | |||
| ??200S -1 | ??30S -1 | ??5S -1 | ??1S -1 | |||||
| The blank group | ??- | ??10 | ??3.84±0.26 | ??5.17±0.37 | ??9.13±0.78 | ??21.02±2.28 | ??0.46±0.03 | ??1.363±0.079 |
| Model control group | ??- | ??11 | ??4.77±0.30# | ??7.09±0.59## | ??14.45±1.86## | ??37.59±4.90## | ??0.49±0.03# | ??1.190±0.038 ** |
| The TIANBAONING matched group | ??0.02 | ??10 | ??4.70±0.39 | ??6.65±0.76 | ??12.00±1.44 ** | ??28.19±3.68 ** | ??0.48±0.02 * | ??1.283±0.016 * |
| Medicine of the present invention | ??4 | ??10 | ??4.83±0.40 | ??6.56±0.76 | ??11.77±0.87 ** | ??27.75±2.69 ** | ??0.50±0.04 | ??1.271±0.074 * |
| Medicine of the present invention | ??2 | ??10 | ??5.16±0.65 | ??7.14±0.70 | ??12.90±0.97 * | ??30.63±2.45 ** | ??0.49±0.03 | ??1.251±0.115 * |
| Medicine of the present invention | ??1 | ??10 | ??4.52±0.68 | ??6.47±0.91 | ??11.75±2.03 ** | ??28.55±5.75 ** | ??0.49±0.03 | ??1.269±0.091 * |
Compare with the blank group: compare with model group #P＜0.05 ##P＜0.01:
*P＜0.05
*P＜0.01
2, acute, long term toxicity test
1), acute toxicity test
Test objective
Medicine of the present invention is by the development of preparation teaching and research room of Beijing University of Chinese Medicine, and this test objective is that its maximum tolerated dose is measured in the acute toxicity effect of observing this medicine.
Medicine medicine of the present invention is provided by preparation teaching and research room of Beijing University of Chinese Medicine, makes 100% suspension with distilled water before the test.
The animal mice, the Kunming kind, totally 36, body weight 18～22g all is female.Available from zooscopy institute of Chinese Academy of Medical Sciences breeding farm, the certificate of competency: the moving word of doctor 01-3001 number.
Method and result
Mice weighed is divided into two groups, and fasting is gastric infusion or ordinary water 20ml/kg after 12 hours, and administration is 3 times in one day, and 6 hours at interval, the total dosage of medicine of the present invention was 60g/kg.Observed 7 days record mice outward appearance behavior variation and appetite, amount of drinking water and body weight after the administration continuously.
Observed 7 continuously after the mouse stomach administration,, do not see that tangible general behavior changes with the matched group ratio.Medicine of the present invention does not all have obvious influence to weight of mice and amount of drinking water and appetite, sees Table 1, table 2, table 3.
Mice body weight change behind the table 1 filling stomach medicine of the present invention
| Group | Number of animals (only) | Body weight (g) before the administration | Body weight after the administration (g) X ± S | |||
| The 1st day | The 3rd day | The 5th day | The 7th day | |||
| The ordinary water contrast | ??18 | ??20.27±1.27 | ??22.11±1.60 | ?25.06±1.80 | ??25.60±2.01 | ??26.11±2.05 |
| Medicine of the present invention | ??18 | ??20.17±1.10 | ??21.56±1.62 | ?24.83±1.65 | ??25.39±1.88 | ??26.56±2.05 |
The mice water yield changed after table 2 was irritated stomach medicine of the present invention
| Group | Number of animals (only) | Amount of drinking water after the administration (ml/ day) | |||
| The 1st day | The 3rd day | The 5th day | The 7th day | ||
| The ordinary water contrast | ??18 | ??114.0 | ??108.5 | ??110.0 | ??109.2 |
| Medicine of the present invention | ??18 | ??109.3 | ??109.3 | ??108.5 | ??112.0 |
Mice appetite changed after table 3 was irritated stomach medicine of the present invention
| Group | Number of animals (only) | Appetite after the administration (g/ day) | |||
| The 1st day | The 3rd day | The 5th day | The 7th day | ||
| The ordinary water contrast | ??18 | ??92 | ??91 | ??82 | ??89 |
| Medicine of the present invention | ??18 | ??98 | ??86 | ??85 | ??82 |
Medicine maximum tolerated dose of the present invention is 60g/kg, is 150 times of people's consumption.Be calculated as follows:
Medicine mice consumption of the present invention:
100% * 20ml/kg * 3 time/day=60g/kg
People's consumption:
24g/60kg day=0.4g/kg
60g/kg÷0.4g/kg＝150
Conclusion: medicine maximum tolerated dose of the present invention is 60g/kg, is 150 times of people's consumption.Medicine of the present invention does not have obvious influence to mice body weight, amount of drinking water, appetite, and behavior does not also have significant change after the mice medication, and medicine filling stomach safety and low toxicity of the present invention are described.
2), long term toxicity test
Experiment purpose
Observe the rat toxic reaction that oral medicine of the present invention produced in continuous two months, to determine clinical application safety.
Experiment material
1, medicine (inspection product): medicine of the present invention, extracting solution dry powder is used in experiment, pale brown color, every g is provided by preparation teaching and research room of Beijing University of Chinese Medicine when in crude drug amount 5.1 grams, is diluted to desired concn with drinking water during administration; Every day matching while using.
2, animal: 80 of wistar kind rats, female average weight are 134.5 ± 9.9g; Female average weight is 133.5 ± 9.6g, and the certificate of competency is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field: the moving word of doctor 01-3008 number.Animal housing's temperature is 25.0 ℃ ± 2.0 ℃.Every day water supply of forage abundance.
3, instrument: Japan produces the f-800 blood counting instrument; C0BAS MIRA 25-4464 biochemistry analyzer.
Experimental technique
1, grouping and medication
Test used 80 rats and be equally divided into 4 groups: normal control group, large, medium and small three the dosage groups of medicine of the present invention, 20 every group, male and female half and half.High dose group orally give every day medicine 10g/kg of the present invention (this dosage is equivalent to 50 times of people's consumption), middle dosage 5g/kg, small dose group 2g/kg, matched group gives the isometric(al) drinking water, continuous two months (8 week), fasting 12h after the last administration, every group 2/3 animal kills inspection, get blood and main organs, carry out relevant index respectively and detect, observing has non-toxic reaction.The residue rat stops the inspection extremely of two week of administration back, has or not the Secondary cases untoward reaction with observation.
2, observation index
(1) general state: observe situations such as rat spirit, behavior, activity, defecation every day during the administration, claims one time one daily inleting appetite during the administration weekly.
(2) body weight: weigh once weekly with convalescent period during the administration.
(3) hematological examination: after the rat administration time limit finishes or after convalescent period, pentobarbital sodium anesthesia, the blood-letting of carotid artery intubate, anticoagulant heparin produce f-800 blood counting instrument mensuration total white blood cells, content of hemoglobin, platelet count totally six indexs with Japan.
(4) serum biochemistry is learned and is checked: get one fen blood sample in addition from above-mentioned rat carotid artery, separation of serum, test with cobas mira 25-4464 automatic biochemical analyzer, comprise that glutamate pyruvate transaminase (GPT), glutamic oxaloacetic transaminase, GOT (GOT), alkali phosphatase (AKP), blood urea nitrogen (BUN), total protein (TP), albumin (ALB), albumin and globulin ratio (A/G), total bilirubin (T-BIL), creatinine (Grea), T-CHOL (T-CHO) amount to ten indexs.
(5) obduction and organ coefficient: after each organizes the rat blood-letting, carry out obduction immediately, each internal organs of gross examination of skeletal muscle have not pathological change, and take out the heart, liver, spleen, lung, kidney, uterus, seven internal organs of ovary, weigh respectively and calculate each organ coefficient (g/kg).
(6) histopathologic examination: with above-mentioned internal organs put into that 20% formalin solution is fixing, 10g/kg and 5g/kg dosage group Rats Organs and Tissues use.Paraffin section, HE dyeing, and carry out the inspection of light microscopic tectology.The internal organs of 2g/kg dosage group rat are equipped with inspection.
Experimental result
1, general state: large, medium and small three the dosage group rat activities during administration of medicine of the present invention are normal substantially, feed (seeing Table 1), amount of drinking water, defecation Non Apparent Abnormality, and none example is dead.
2, body weight: no significant difference between weight gain value and the matched group during the rat administration of three dosage groups of medicine of the present invention.(P＞0.05 sees Table 2).
3, hematological examination: the administration of three dosage groups of medicine of the present invention rat is after 2 months and after convalescent period, and 6 indexs of hematology all in range of normal value, compare there was no significant difference (P＞0.05 sees Table 3) with matched group.
4, serum biochemistry learn to be checked: three dosage groups of medicine of the present invention and matched group relatively all do not have explicitly difference (P＞0.05 sees Table 4) in biochemical ten indexs of serum after administration February and after recovering.
5, main organs inspection: administration after 2 months and convalescent period after the rat obduction, organize the internal organs outward appearance to show no obvious abnormalities, 10g/kg and two dosage groups of 5g/kg male rat spleen organ index are less than matched group (P＜0.01) in the organ coefficient result of calculation, all the other each organ indexs all with matched group no significant difference (P＞0.05, table 5).
6, clean tissue is learned and is checked:
(1) administration Rats Organs and Tissues morphological examination in 2 months result shows: administration group rat and the rats in normal control group heart, liver, spleen, lung, kidney there is no pathological change (initial report See Attachment 1, adnexa two).
(2) drug withdrawal 2 week back Rats Organs and Tissues morphological examination result shows: each internal organs of administration group rat and rats in normal control group there is no pathological change (initial report sees Appendix two, adnexa four).
The result: medicine 10g/kg of the present invention, 5g/kg and 2g/kg successive administration 2 months, main organs (heart, liver, spleen, lung, kidney) is not all found the toxicity pathologic damage with relevant internal organs (ovary, uterus).Do not see the Secondary cases pathological changes after the drug withdrawal after 2 weeks yet.
Discuss and conclusion
This experiment is according to " provisions for new drugs approval " supplementary provisions documents such as " study of tcm new drug guides "
[1] [2] [3], clinical consumption, the course of treatment of medicine according to the present invention, determine that adopting high dose is 10g/kg, this dosage is 50 times of clinical people's consumptions, and middle dosage is 5g/kg, and low dose is 2g/kg (this dosage is greater than the effect experiment effective dose), successive administration 2 months has been observed every index on request.The result shows: rat diet, growth, hematological indices, serum biochemistry are learned all no abnormal change of index, the overt toxicity reaction is not all found in the inspection of most of main organs exponential sum pathomorphology, wherein big or middle dosage male rat index and spleen index is less than matched group, but this internal organs pathomorphism Non Apparent Abnormality, the no overt toxicity effect in used dosage and administration time of result of the test explanation medicine of the present invention.
Medicine long term toxicity of the present invention (2 months) experimental pathology visual report
One, matched group (female, each 7 of heros, totally 14)
This organizes female male identical internal organs does not have obvious histology's difference.
1, heart: the cardiac muscle fiber short cylinder, branch is arranged, band is arranged, marshalling, endochylema is abundant.Acidity, the nucleus ellipse is positioned at central authorities.Blood capillary is abundant, is distributed between the cardiac muscle fiber.
2, liver: lobules of liver clear in structure and neat.The liver rope is radial arrangement around central vein, the hepatocyte polygon, and endochylema is abundant, the acidophilia.Its nucleolus is positioned at central authorities, and chromatin is sparse evenly, visible sometimes kernel.It is complete that portal area three connects structure.
3, spleen: tunicle is not thick, and girder is clear.White pulp is made up of lymphatic nodule and periarterial lymphatic sheath, and the intensive and ripe red pulp of lymphocyte comprises medullary cord and medullary sinus, is rich in blood, visible sometimes multinucleated giant cell.
4, lungs: alveolar dashes and is full of, and does not have in the alveolar space and oozes out, and covers alveolar epithelial cells (I and II type) in the alveolar wall, and alveolar septum is not thick, includes blood capillary.Bronchus at different levels, the trachea structure is normal, and artery and vein companion many and appropriate level goes.
5, kidney: renal cortex is rich in glomerule, and its constituent does not have hypertrophy, and glomerule does not have sclerosis, and no demilune forms.The renal tubules system structure is normal, and the tubule epithelium does not have degeneration, necrosis, no protein cast in the tube chamber, no erythrocyte or crystallization.Matter NIP cellular infiltration between kidney, blood capillary is abundant, and the kidney small artery does not have sclerosis.
6, ovary: ovarian cortex is thicker, in see the follicle of different developmental phases, corpus luteum is big, similar round, visible sometimes lean type.Medullary substance is narrow and small, is rich in blood vessel.
7, uterus: by serous coat, flesh layer and inner membrance are formed, and the flesh layer is made up of belt and longitudinal muscle, and inner membrance is thicker relatively, and body of gland is sparse relatively, all contains the eosinophilic granulocyte of some in each layer.
Two, medicine 10g/kg of the present invention (female, each 7 of heros, totally 14)
Do not have between the identical internal organs of male and female in this group and obviously organize filial piety difference.
1, heart: structure is normal, with the matched group zero difference.Cardiac muscle fiber does not have degeneration necrosis, and NIP cellular infiltration, blood vessel do not have expansion and ooze out.
2, liver: structure is with the matched group unanimity.The lobules of liver structural integrity, hepatocyte does not have degeneration necrosis, and sinus hepaticus does not have dilatation and congestion, and the hole parietal cell does not have hypertrophy, portal area NIP cellular infiltration, no biliary ductuli hypertrophy.
3, spleen: structure is normal.The lymphocyte maturation of white pulp, no hypertrophy.It is medium that red pulp contains blood volume, no fibrous connective tissue hypertrophy.
4, lungs: alveolar filling, intracavity do not have and ooze out, and alveolar epithelium does not have hypertrophy, and alveolar septum does not have and thickens.Bronchial epithelial cells at different levels do not have degeneration necrosis, and tube wall does not have fibrosis.Blood capillary is abundant, no dilatation and congestion.
5, kidney: each constituent of glomerule does not have hypertrophy, and no demilune forms, and glomerule does not have sclerosis, and sacculus does not have adhesion.The glomerule parietal cell does not have degeneration necrosis, and intracavity does not have cast.Matter NIP cellular infiltration between kidney, blood vessel does not have sclerosis, compares no significant difference with the matched group corresponding organs.
6, ovary: structure is normal.Follicles at different levels are apparent, and corpus luteum is justified greatly, and lutein cell is abundant.Rich blood vessel does not have the fibrous connective tissue hypertrophy in the medullary substance.
7, uterus: structure is with the matched group unanimity.
Three, medicine 5g/kg of the present invention (female, male each 7)
No obvious histology's difference between the female male rat of identical internal organs in this group.
1, cardiac muscle: structure is normal, and is consistent with heavy dose of experimental group with matched group.
2, liver: hepatocyte does not have degeneration necrosis.Organizational structure is with matched group and heavy dose of group no significant difference.
3, spleen: structure is normal, and is consistent with heavy dose of group with matched group.
4, lungs: the same matched group of organizational structure, heavy dose of group no significant difference.
5, kidney: structure is normal.
6, ovary: organizational structure is consistent with heavy dose of group with matched group.
7, uterus: each hierarchical structure is with matched group and heavy dose of group no significant difference.
Conclusion is finding to sum up, and the matched group and the administration group heart, liver, spleen, lung, kidney, ovary, each organs and tissues structure no significant difference of uterus are normal.Organize also zero difference between the female male identical internal organs.Show that for a long time taking (2 months) medicine of the present invention does not have obvious toxic-side effects.
Medicine convalescent period pathology of the present invention report (administration February after two weeks of drug withdrawal)
One, matched group (female, male each 3)
Female male identical internal organs do not have obvious histology's difference in this group.
1, heart: cardiac muscle fiber short cylinder, marshalling have branch, band are arranged.Myocardial cell cytoplasm is abundant, and the nucleus ellipse is positioned at the central authorities of cell; Blood capillary is abundant, between cardiac muscle fiber.
2, liver: lobules of liver is neat, clear in structure.The liver rope is radial arrangement, hepatocyte polygon, cytoplasmic granule shape, acidophilia around central vein; The karyon circle is positioned at cell central authorities, and chromatin is sparse, evenly, and visible sometimes kernel; Be sinus hepaticus between liver cell plate, include blood flow; It is complete that portal area three connects structure.
3, spleen: tunicle is not thick, and girder is clear.Lymphatic nodule and periarterial lymphatic sheath constitute white pulp, and lymphocyte is abundant and ripe; Red pulp is made up of medullary cord and medullary sinus, is rich in blood, visible sometimes multinucleated giant cell.
4, lungs: alveolar filling, alveolar wall built-in alveolar epithelium, alveolar septum is rich in blood capillary.Bronchus at different levels artery and vein companion many and appropriate level go.
5, kidney: the glomerule structure is normal, and each constituent does not have hypertrophy; The renal tubules system structure is also normal, and the tube wall cell does not have degeneration, necrosis, and intracavity does not have cast; Between the matter NIP soak into, blood vessel does not have sclerosis.
6, uterus: by serous coat, flesh layer and theca interna are formed.The theca interna thickness differs, and relevant with hormonal readiness, each layer is dispersed in the eosinophilic granulocyte.
7, ovary: cortex is thicker, includes the follicle and the big and round corpus luteum of different developmental phases; Medullary substance is thinner, includes blood vessel, nerve etc.
Two, medicine of the present invention (10g/kg)
In this group, female, male phase is with no obvious histology's difference between internal organs.
1, heart: structure is normal, same matched group.
2, liver: structure is normal, with the matched group unanimity.
3, spleen: structure is normal, same matched group.
4, lungs: structure is normal, with the matched group unanimity.
5, kidney: structure is normal, with the matched group zero difference.
6, uterus: structure is normal, compares zero difference with matched group.
7, ovary: organizational structure is with the matched group unanimity.
Three, medicine of the present invention (5g/kg)
There is not significant difference between the identical internal organs of female male rat in this group.
1, cardiac muscle: no degeneration, necrosis, structure is consistent with the first two group.
2, liver: structure is normal, and is consistent with the first two group.
3, spleen: the same matched group of structure, heavy dose of group corresponding organs unanimity.
4, lungs: structure is organized with the first two, all belongs to normal.
5, kidney: structure is normal, the same two groups of zero differences.
6, uterus, ovary: structure is all normal, with the heavy dose of group of matched group zero difference.
Conclusion is finding to sum up, and the matched group and the administration group heart, liver, spleen, lung, kidney, ovary, uterine cancer cell structure no significant difference are normal.Organize also zero difference between the female male identical internal organs.Show and have no adverse reaction after taking medicine drug withdrawal of the present invention for a long time.
The specific embodiment
Further specify technical scheme of the present invention below by specific embodiment.
Embodiment 1
40 parts of 24 parts of Rhizoma Corydalis of Radix Salviae Miltiorrhizae 60 portions of Rhizoma Cyperis of 60 portions of Radix Paeoniae Albas (processed with vinegar) (processed with vinegar)
24 parts in Fructus Toosendan (stir-fry) 10 portions of Radix Glycyrrhizaes of 20 parts of Fructus Foeniculi (processed with honey)
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet or capsule according to this area routine techniques.
Embodiment 2
50 parts of 30 parts of Rhizoma Corydalis of Radix Salviae Miltiorrhizae 75 portions of Rhizoma Cyperis of 75 portions of Radix Paeoniae Albas (processed with vinegar) (processed with vinegar)
30 parts in Fructus Toosendan (stir-fry) 12.5 portions of Radix Glycyrrhizaes of 25 parts of Fructus Foeniculi (processed with honey)
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet or capsule according to this area routine techniques.
Embodiment 3
60 parts of 36 parts of Rhizoma Corydalis of Radix Salviae Miltiorrhizae 90 portions of Rhizoma Cyperis of 90 portions of Radix Paeoniae Albas (processed with vinegar) (processed with vinegar)
36 parts in Fructus Toosendan (stir-fry) 15 portions of Radix Glycyrrhizaes of 30 parts of Fructus Foeniculi (processed with honey)
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet or capsule according to this area routine techniques.
Embodiment 4
80 parts of 48 parts of Rhizoma Corydalis of Radix Salviae Miltiorrhizae 120 portions of Rhizoma Cyperis of 120 portions of Radix Paeoniae Albas (processed with vinegar) (processed with vinegar)
48 parts in Fructus Toosendan (stir-fry) 20 portions of Radix Glycyrrhizaes of 40 parts of Fructus Foeniculi (processed with honey)
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet or capsule according to this area routine techniques.
Embodiment 5
Radix Salviae Miltiorrhizae 600g Radix Paeoniae Alba 600g Rhizoma Cyperi (processed with vinegar) 240g Rhizoma Corydalis (processed with vinegar) 400g
Fructus Toosendan (stir-fry) 200g Fructus Foeniculi 100g Radix Glycyrrhizae (processed with honey) 240g
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule according to this area routine techniques.
Embodiment 6
Radix Salviae Miltiorrhizae 750g Radix Paeoniae Alba 750g Rhizoma Cyperi (processed with vinegar) 300g Rhizoma Corydalis (processed with vinegar) 500g
Fructus Toosendan (stir-fry) 250g Fructus Foeniculi 125g Radix Glycyrrhizae (processed with honey) 300g
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density is 1.35～1.38 (60～65 ℃), drying under reduced pressure (0.08Mpa, 60～70 ℃), pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule according to this area routine techniques.
Claims (6)
1, a kind of Chinese medicine composition for the treatment of dysmenorrhea is characterized in that: it is to be prepared from by the following weight proportion raw material:
Radix Salviae Miltiorrhizae 60-120 part Radix Paeoniae Alba 60-120 part Rhizoma Cyperi (processed with vinegar) 24-48 part Rhizoma Corydalis (processed with vinegar) 40-80 part
Fructus Toosendan (parched) 20-40 part Fructus Foeniculi 10-20 part Radix Glycyrrhizae (processed with honey) 24-48 part.
2, Chinese medicine composition as claimed in claim 1 is characterized in that: the weight proportion of described raw material is:
Radix Salviae Miltiorrhizae 70-90 part Radix Paeoniae Alba 70-90 part Rhizoma Cyperi (processed with vinegar) 25-36 part Rhizoma Corydalis (processed with vinegar) 40-60 part
Fructus Toosendan (parched) 20-30 part Fructus Foeniculi 10-15 part Radix Glycyrrhizae (processed with honey) 25-36 part.
3, Chinese medicine composition as claimed in claim 2 is characterized in that: the weight proportion of described raw material is:
50 parts of 30 parts of Rhizoma Corydalis (processed with vinegar) of 75 parts of Rhizoma Cyperi (processed with vinegar) of 75 portions of Radix Paeoniae Albas of Radix Salviae Miltiorrhizae
30 parts of 12.5 parts of Radix Glycyrrhizae (processed with honey) of 25 parts of Fructus Foeniculi of Fructus Toosendan (parched).
4, any described Chinese medicine composition of claim 1-3, it is characterized in that: its dosage form is tablet, capsule, granule.
5, the preparation method of any described Chinese medicine composition of claim 1-3, it is characterized in that: this method comprises the steps:
More than seven flavor crude drug, get Rhizoma Cyperi, Fructus Foeniculi and soaked 6 hours, vapor distillation extracts volatile oil, the volatile oil after the distillation is with the beta cyclodextrin of 6 times of amounts, under 40 ℃ of conditions, adopt the saturated water solution method inclusion after, drying for standby, medicinal liquid filtration; Get the Radix Paeoniae Alba with 50% ethanol, extract secondary, each 1 hour, each 6 times of amounts; Rhizoma Corydalis extracts three times with 70% ethanol, and each 1 hour, each 4 times of amounts; Extracting solution filters, and merges, and reclaims ethanol; Radix Salviae Miltiorrhizae extracts secondary with 85% ethanol, and 1.5 hours for the first time, 8 times of amounts; 1 hour for the second time, 6 times of amounts, extracting solution filters, and reclaims ethanol; Medicinal residues and Fructus Toosendan, Radix Glycyrrhizae decoct with water secondary after the Radix Salviae Miltiorrhizae alcohol extraction, and each 1 hour, 6 times of amounts, medicinal liquid filters; Merge with above-mentioned four kinds of medicinal liquids, being concentrated into relative density 60-65 ℃ survey is 1.35-1.38,0.08Mpa, 60-70 ℃ of following drying under reduced pressure, pulverize and be fine powder, add the beta cyclodextrin inclusion complex that dextrin reaches Rhizoma Cyperi and Fructus Foeniculi volatile oil in right amount, mixing is made granule, tablet, capsule according to this area routine techniques.
6, as the application of any described Chinese medicine composition of claim 1-3 in the property the sent out dysmenorrhea of preparation treatment source.
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| CNB2005100693152A CN100335102C (en) | 2005-05-13 | 2005-05-13 | Chinese medicina composition for treating algomenorrhea and its preparation method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784263A (en) * | 2011-05-18 | 2012-11-21 | 北京亚东生物制药有限公司 | Method for detecting traditional Chinese medicinal composition for treating dysmenorrhoea |
| CN102788862A (en) * | 2011-05-18 | 2012-11-21 | 北京亚东生物制药有限公司 | Method for detecting traditional Chinese medicinal composition for treating dysmenorrhea |
| CN104971137A (en) * | 2015-06-23 | 2015-10-14 | 肖庆义 | Traditional Chinese medicinal composition for treating menstrual distending pains of breasts, and preparation method and use thereof |
| CN105343412A (en) * | 2015-12-15 | 2016-02-24 | 李国深 | Traditional Chinese medicinal composition for treating dysmenorrhea |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1425457A (en) * | 2003-01-02 | 2003-06-25 | 濮桂宝 | Granular preparation for dysmenorrhea |
-
2005
- 2005-05-13 CN CNB2005100693152A patent/CN100335102C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784263A (en) * | 2011-05-18 | 2012-11-21 | 北京亚东生物制药有限公司 | Method for detecting traditional Chinese medicinal composition for treating dysmenorrhoea |
| CN102788862A (en) * | 2011-05-18 | 2012-11-21 | 北京亚东生物制药有限公司 | Method for detecting traditional Chinese medicinal composition for treating dysmenorrhea |
| CN102784263B (en) * | 2011-05-18 | 2015-06-10 | 北京亚东生物制药有限公司 | Method for detecting traditional Chinese medicinal composition for treating dysmenorrhoea |
| CN104971137A (en) * | 2015-06-23 | 2015-10-14 | 肖庆义 | Traditional Chinese medicinal composition for treating menstrual distending pains of breasts, and preparation method and use thereof |
| CN105343412A (en) * | 2015-12-15 | 2016-02-24 | 李国深 | Traditional Chinese medicinal composition for treating dysmenorrhea |
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| Publication number | Publication date |
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| CN100335102C (en) | 2007-09-05 |
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